Carboxamides

ABSTRACT

Process for manufacture of tetramisole and corresponding nitrophenyl, aminophenyl and tolyl derivatives, which comprises ring-closing a 2-imino-3-(2-amino-2-phenylethyl)thiazolidine derivative, e.g. by heating said thiazolidine derivative under reflux in water at a pH below 8. Two processes for manufacture of said thiazolidine derivatives used as intermediates: (a) hydrolysis of corresponding acylamino derivative, (b) reacting an N-(2-amino-2-phenylethyl)-ethylamine derivative with thiourea or a thiocyanate or isothiocyanate.

United States Patent McMenim Dec. 9, 1975 C ARBOXAMIDES I 75] Inventor:Michael Edward McMenim, Primary Examiner Harry Moan Attorney. Agent, orFirm-Cushman, Darby &

Macclesfield, England Cushman [73] Assignee: Imperial ChemicalIndustries Limited, London, England [22] Filed: May 31, 1974 [57]ABSTRACT Appl. No.: 475,272

Related US. Application Data Division of Ser, No, 270,928, July 10,1972, Pat. No 3.841070.

Foreign Application Priority Data July 27, l97l United Kingdom 35206/7lU.S. CL 260/457; 260/558 P; 260/562 R lnt. Cl. ..C07C 103/44; CO7ClO3/82;

C07C l4l/O2 Field of Search 260/558, 562, 457

References Cited UNITED STATES PATENTS 8/1964 Krapcho H 260/562 Processfor manufacture of tetramisole and corresponding nitrophenyl,aminophenyl and toly] derivatives, which comprises ring-closing a2-imin0-3-(2- amino-2-phenylethyl)thiazolidine derivative, e.g. byheating said thiazolidine derivative under reflux in water at a pH below8. Two processes for manufacture of said thiazolidine derivatives usedas intermediates: (a) hydrolysis of corresponding acylamino derivative,(b) reacting an N-(Z-amino-Z-phenylethyl)-ethylamine derivative withthiourea or a thiocyanate or isothiocyanate.

7 Claims, No Drawings CARBOXAMIDES This is a division of applicationSer. No. 270,928, filed July 10, i972 and now US. Pat. 3,845,070.

Tetramisole, i.e., dl-2,3,5,6-tetrahydro-6-phenylimidazo[2,l-b]thiazole, and its pharmaceutically-acceptableacid-addition salts, and the corresponding laevorotatory compounds, andcorresponding nitrophenyl, aminophenyl and tolyl derivatives, are knownto have anthelmintic activity. This invention relates to a new processfor the manufacture of tetramisole and analogues thereof, and saltsthereof, and to new intermediates used in said new process, and toprocesses for their manufacture.

According to the invention there is provided a pro- -cess for themanufacture of compounds of the formula:

ble acid-addition salts thereof, which comprises ringclosing a compoundof the formula:

wherein R has the meaning stated above and R stands 2 for hydrogen or analkyl, alkenyl, aralkyl or aryl radical, or an acid-addition saltthereof.

When R stands for a nitrophenyl, aminophenyl or tolyl radical it may be,for example, a m-nitrophenyl, m-aminophenyl or m-tolyl radical. When Rstands for an alkyl or alkenyl radical it may be, for example, one ofnot more than five carbon atoms, for example a methyl, ethyl, isopropyl,isobutyl, isoamyl, 3-pentyl or allyl radical. When R stands for an arylor aralkyl radical it may be, for example, one of not more than 10carbon atoms, for example a phenyl or benzyl radical.

The said ring-closure may be carried out in several alternative ways. Inone alternative the thiazolidine starting material is reacted in waterat an elevated temperature, for example at to l50C., for example underreflux, and at a pH below 8, and preferably at a pH of 2 to 4. inanother alternative (only applicable when R stands for hydrogen) thethiazolidine starting material is reacted in water with nitrous acid,and this reaction is preferably carried out at approximately roomtemperature. The nitrous acid may be formed in situ in the reactionmixture by the use of a nitrite, for example an alkali metal nitrite,and an acid, for example an inorganic acid, for example hydrochloricacid. In another alternative the thiazolidine starting material isheated at 200 to 300C, and more particularly at 230 to 260C. In thisalternative the starting material may be heated alone or it may beheated in the presence of an inert diluent which is stable at 200 to300C, for example a mixture of diphenyl and diphenyl ether. In anotheralternative the thiazolidine starting material is heated at to l50C. ina dipolar aprotic solvent, for example dimethylformamide.

It is believed that the above-mentioned ring-closure process proceeds bythe following mechanism (except in the alternative involving nitrousacid):

l CH.CH

or an acid-addition salt thereof or a protonated derivative thereoftetramisn'le oranalogue (protona'ted form) VII .CH .SH

wherein R and R have the meanings stated above and X stands for ananion.

A specific compound of the formula VII is, for example2-amino-3-(Z-mercaptoethyl)-S-phenylimidazole hydrochloride.

The compounds of the formula VII, wherein R, R and X have the meaningsstated above, can be obtained by adjusting an aqueous solution of anacid-addition salt of the formula II, wherein R and R have the meaningsstated above, to pH 7, and isolating the product in conventional manner.

According to a further feature of the invention there are providedcompounds of the formula II, wherein R and R have the meanings statedabove, and acid-addition salts thereof.

Preferred compounds of the formula II are 2-imino- 3-( Z-amino-Z-phenylethyl )thiazolidine dihydrochloride,2-allyl-imino-3-(2-amino-2-phenylethyl)thiazolidine dihydrochloride and2-methylimino-3-(2-amino- Z-phenylethyl)thiazolidine dihydrochloride.

According to a further feature of the invention there is provided aprocess for the manufacture of compounds of the formula II, wherein Rand R have the meanings stated above, and acid-addition salts thereof,which comprises hydrolysing a compound of the formula:

1 l R .CH.CH

wherein R and R have the meanings stated above, and R stands forhydrogen or an alkyl, aryl or aralkyl radical, or an acid-addition saltthereof, under acidic conditions.

When R stands for an alkyl radical it may be, for example, an alkylradical of not more than five carbon atoms, for example a methylradical. When R stands for an aryl or aralkyl radical it may be, forexample, an aryl or aralkyl radical of not more than carbon atoms, forexample a phenyl or benzyl radical. Suitable hydrolytic agents areaqueous solutions (preferably with a Hammett acidity function belowzero) of strong VIII acids, for example hydrochloric, hydrobromic orsulphuric acid. The hydrolysis is conveniently carried out at about-l20C., for example under reflux.

The starting materials of the formula VIII may be obtained as outlinedbelow, and as described in more detail in the Examples:

NHCOR" NHCOR In these formulae R, R and R have the meanings statedabove, X stands for a chlorine or bromine atom or a hydroxy radical, andY stands for a chlorine or bromine atom or a hydrogen-sulphato radical(OSO;,H).

According to a further feature of the invention there is provided aprocess for the manufacture? of compounds of the formula II, wherein Rand R have the meanings stated above, and acid-addition salts thereof,which comprises reacting a compound of the formula:

VIII

wherein R and Y have the meanings stated above, or an acid-addition saltthereof, with thiourea or a compound of the formula R NCS, wherein R hasthe meaning stated above.

This process is conveniently carried out in the presence of water, andoptionally an alkanol 0f t more than 5 carbon atoms, for exampleethanol. be P ent also. In the case where the sulphur-containin 3 tantis thiourea, the process is carried 0111 at 30 t0 C, for example underreflux, and 111 P 5, which may be provided by the presenf fh reaFtlonmixture of an appropriate amoy g'" g zl l f organic acid, for example 2)y me one '1. the case where the sulphur- -toluenesulphonic acidEontainin g reactant is R NCS. the Teacno" y be ditions i.e. at t d rbasic to mildly a f gl l fi i o in the case wher Stands for hydrogen(i.e., R NCS is thiocyanic acid) the may be used a corresponding salt,i.e., a th yf example monium thimyanate or an alkall metal th|ocyanate,for example Sodium or assium thiocyanate, at a pH of O to gc tials ofthe formula x11 can be 01 tail in the Examples:

.be mentioned, for example,

-continued w" Xlll PCl or SOCl, (for (=Cl) or PBr, (for Y=Br) or H 50(for Y=OSO H) According to a further feature of the invention there areprovided compounds of the formula X, wherein R, R and Y have themeanings stated above, and acidaddition salts thereof.

As specific compounds of the formula X there may N-( 2-acetylamino-2-phenylethyl)-ethanolamine-O-sulphate, and the analogous2-phenylacetylamino-and 2-benzoylamino derivatives, and N-(2-acetylamino-Z-phenylethyl)-2-chloroethylamine.

According to a further feature of the invention there is provided aprocess for the manufacture of compounds of the formula X, wherein R, Rand Y have the meanings stated above, and acid-addition salts thereof,which comprises reacting a compound of the formula IX, wherein R and Xhave the meanings stated above, or an acid-addition salt thereof, with acompound of the formula R CN, wherein R has the meaning stated above, inthe presence of concentrated sulphuric acid at 20C. to 60C., andpreferably at lC. to 25C. In the case where R stands for hydrogen theremay be used a corresponding salt, for example ammonium cyanide or analkali metal cyanide, for example sodium or potassium cyanide.

The invention is illustrated but not limited by the following Examples:

EXAMPLE 1 Sulphuric acid (98% wlw; 80g.) was added to acetonitrile(12.3g.) with stirring below C. The solution was cooled to l0C., andN-(2-hydroxy-2-phenylethyl)ethanolamine 18. lg.) was added in portionsover 15 minutes, maintaining the temperature below 0C. The reactionmixture was stirred at 0C. for 1 hour and then at 25C. for 2 hours. Themixture was then poured onto ice (200 g.) and the resulting mixtureadjusted to pH 5 with l8N-sodium hydroxide, adding ice to keep thetemperature below 10C. The solution was evaporated to dryness at 50C.]mm. The residue was extracted with ethanol (SOOmL), and the extract wasfiltered and the filtrate evaporated at 50C. in vacuo to dryness. Theresidue was dissolved in boiling ethanol (l00ml.), and the solutionallowed to cool to room temperature. The resulting crystals werefiltered off, washed once with ethanol (ml.), and dried at 70C. to giveN-( 2-acetylamino-2-phenylethyl)ethanolamine- O-sulphate, m.p.2 l 0-2l2C.

EXAMPLE 2 3-( 2-Acetylamino-2-phenylethyl )-2-iminothiazolidine (2g) wasdissolved in SN-hydrochloric acid (l5 ml. and the solution refluxed for6 hours. The solution was evaporated to dryness at 60C./l5mm. to give acrystalline solid, which was dissolved in ethanol (20ml.) and thesolution refluxed for 5 minutes. The solution was cooled to roomtemperature, the resulting mixture filtered. and the crystalline residuewashed 6 with ethanol (20ml.) and dried at 50C. to give 3-(2-amino-2-phenylethyl)-2- iminothiazolidine dihydrochloride, m.p.202205C.

The thiazolidine derivative used as starting material was obtained asfollows:

A solution of N(2-acetylamino-2- phenylethyl)ethanol-amine-O-sulphate(3.02g.) in water 10ml.) was added to a solution of sodium hydroxide(1.2g) in water 10ml.) at C. The solution was refluxed for 30 minutesand then cooled and extracted with methylene dichloride (2 X 20ml.). Thecombined extracts were dried over anhydrous sodium sulphate andevaporated at 30C. in vacuo to give a white solid. This was crystallisedfrom ethyl acetate to give N-(2-acetylamino-2- phenylethyl)aziridine,m.p. l l4l l6C.

The said aziridine derivative (0.5 lg.) was added to a stirred solutionof thiourea (0.228g.) and sulphuric acid (98% wlw; 0.14mi.) in water(3ml.) at 20C. The solution was allowed to stand at room temperature forl0 minutes and then heated on the steam bath for 4 hours. The solutionwas cooled and made alkaline (pH ll) with lSN-sodium hydroxide,extracted with methylene dichloride;(2 20ml.), and the combined extractsevaporated to dryness at 30C. in vacuo. The residue was dissolved inbenzene (5ml.), and the product precipitated by addition of ether(5ml.). The precipitate was filtered off, washed with ether (5ml.), andallowed to dry in air at room temperature to give 3-(2-acetylamino-2-phenylethyl )-2-iminoth iazolidine m.p.l36-l38C.

EXAMPLE 3 3-(2-amino-2-phenylethyl)-2-iminothiazolidine dihydrochloridelg.) was dissolved in water (l0ml.) and the solution refluxed for l6hours. The solution was then basified to pH 1 1 with ZN-sodiumhydroxide, extracted with methylene dichloride (2 X 20ml), the combinedextracts dried with anhydrous sodium sulphate and evaporated to drynessat 30C. in vacuo. The residue was dissolved as much as possible inbenzene (20ml.), the mixture filtered, and a saturated solution ofhydrogen chloride in isopropanol added to the filtrate until it had pH2-3. The resulting white precipitate was filtered off, washedsuccessively with benzene (5ml.) and ether (5ml.) and dried in air atroom temperature to give tetramisole hydrochloride, m.p.255258C. Aftercrystallisation from ethanol, a sample had m.p.258260C.

EXAMPLE 4 Sulphuric acid (98% w/w; g.) was added to stirred benzylcyanide (39g) at a temperature below 5C. The solution was cooled tolOC., and N-(2-hydroxy-2- phenylethyl)-ethanolamine (18. lg.) was addedin portions over 15 minutes, maintaining the temperature below 0C Thereaction mixture was stirred at 0C. for 1 hour, and then at 25C. for 2hours. The mixture was poured onto a stirred mixture of ice (200g) andethyl acetate (200ml.). The resulting white precipitate was filteredoff, washed successively with ethyl acetate (200ml.) and water (200ml.),and then crystallised from water to giveN-(2-phenylacetylamino-2-phenylethyl)ethanolamine-O-sulphate,m.p.228229C.

In a similar manner. using an equivalent amount of phenyl cyanide inplace of the benzyl cyanide, there was obtainedN-(Z-benzoylamino-Z-phenylethyl)ethanolamine-O-sulphate m.p.23o-239C.

EXAMPLE 2-Methylimino-3-( 2-phenylacetylamino-Z-phenylethyl)thiazolidine (3.53g.) was dissolved in SN-hydrochloricacid lSml.) and the solution was refluxed for 9 hours. The solution wasevaporated to dryness at 60C. in vacuo and the crystalline residue wascrystallised from ethanol, washed successively with ethanol (5ml.) andacetone (ml.), and dried at 80C., to give 3-(2-amino-Z-phenylethyl)-2-methyliminothiazolidine dihydrochloride, m.p. I95-l98C.

The same product was obtained by hydrolysing 3-(2- acetylamino-2-phenylethyl )-2-methyliminothiazolidine by the method describedimmediately above.

The thiazolidine derivatives used as starting materials were obtained asfollows:

N-( 2-phenylacetylamino-2-phenylethyl)ethanolamine-O-sulphate (7.56g.)was suspended in water (ml. and 2N-sodium hydroxide was added to pH 9. Asolution of methyl isothiocyanate (2ml.) in ethanol (l0ml.) was thenadded dropwise to the stirred solution, and stirring was continued for 2hours at room temperature. The solution was adjusted to pH 12 withl8Nsodium hydroxide, extracted with methylene dichloride (2 X ml.), thecombined extracts dried with anhydrous sodium sulphate, and evaporatedto dryness at C./l5mm. The solid residue was dried in air at roomtemperature to give 2methylimino-3-( 2-phenylacetylamino-Z-phenylethyl)thiazolidine. A sam ple recrystallisedfrom a mixture of benzene and petroleum ether (b.p.60-80C.) hadm.p.144l45C.

In a similar manner, using an equivalent amount of N-(Z-acetylamino-Z-phenylethyl)ethanolamine-O-sulphate in place of theabove-mentioned phenylacetylamino analogue, there was obtained 3-( 2-acetylamino-2-phenylethyl )-2-methyliminothiazolidine. A sample wascrystallised from a mixture of benzene and petroleum ether(b.p.80-l00C.), and then had rn.p. l30-l33C.

EXAMPLE 6 3-( Z-Amino- Z-phenylethyl )-2-methyliminothiazolidinedihydrochloride (1.54g.) was dissolved in water (l0ml.) and the solutionrefluxed for 22 hours, maintaining the pH of the solution at 4 i l byperiodic addition of 2N-sodium hydroxide. The solution was then adjustedto pH 11 with ZN-sodium hydroxide, extracted with methylene dichloride(2 X 20 ml. and the combined extracts dried (Na SO.,) and evaporated todryness at 30C./l5mm. The residue was dissolved as much as possible inbenzene (20ml.), the mixture filtered, and the filtrate adjusted to pH2-3 by the addition of a saturated solution of hydrogen chloride inisopropanol. The resulting white precipitate was filtered off, washedwith chloroform 10ml. and dried in air at room temperature to givetetramisole hydrochloride, m.p.255-258C.

EXAMPLE 7 3-( 2-Amino-2-phenylethyl )-2-iminothiazolidinedihydrochloride (0.75g.) was dissolved in water (4.0ml. and sodiumnitrite (0.40g.) was added. The solution was stirred until the sodiumnitrite had dissolved, and SN-hydrochloric acid (0.20ml.) was thenadded. Samples (about Spl.) of the resulting solution were then appliedto thin layer chromatographic plates made up from Merck silica gel OF254. The plates were eluted with a solvent made up from toluene (50parts by volume), acetone (50 parts by volume), and ammonium hydroxide(specific gravity 0.880; 1.5 parts by volume). The products of thereaction were identified by comparison with authentic samples using Rvalues and the characteristic colours obtained on spraying the plateswith a mixture of equal parts of a 0.3% w/v aq ueous solution ofchloroplatinic acid and a 6% w/v aqueous solution of potassium iodide.The products of the reaction were thus shown to be tetramisole,2-imino-3- styrylthiazolidine and 2-imino-3-(2-hydroxy-2-phenylethyl)thiazolidine, in the approximate ratio of 1:1:2.

EXAMPLE 82-Methylimino-3-(2-phenylacetylamino-2-phenylethyl)-thiazolidine (3.0g)was suspended in a mixture of water (7.5ml.) and aqueous hydrobromicacid (48% w/w; 7.5ml.) and refluxed for 10 hours. The resulting solutionwas evaporated to dryness at 15mm. and the crude product crystallisedfrom isopropanol to give 3- (2-amino-2-phenylethyl)-2-methyliminothiazolidine dihydrobromide, m.p.236238C.

EXAMPLE 9 3-( 2-Amino-2phenylethyl )-2-methyliminothiazolidinedihydrobromide (0.50g.) was dissolved in water (5ml.) and the solutionwas refluxed for l8 hours. The solution was evaporated to dryness at15mm. lsopropanol (20ml.) was added to the residue, the mixture wasrefluxed for 5 minutes and then allowed to cool to room temperature. Theresulting mixture was filtered and the solid residue was washed withacetone (5ml.) and dried at 50C. to give tetramisole hydrobromide,m.p.238242C. (decomposition).

EXAMPLE l02-Ethylimino-3-(2-phenylacetylamino-2-phenylethyl)thiazolidine (10.2g.)and SN-hydrochloric acid (40ml.) were refluxed for l0 hours, and theresulting solution was evaporated to dryness at 15mm. The residue wascrystallised from isopropanol (50ml.) to give 2-ethylimino-3-(2-amino-2-phenylethyl )thiazolidine dihydrochloride, m.p. 1 88 1 9 1C.

This dihydrochloride (1.0g.) was dissolved in water (2ml.) and basifiedto pH 10 with aqueous ammonia solution (specific gravity 0.880). The oilwhich precipitated was extracted with methylene chloride (20ml.). Theextract was dried (MgSO and evaporated to dryness at 15mm. to give2-ethylimino-3-(2-amino-2- phenylethyl)thiazolidine as a colourless oil.The infrared spectrum of the oil had strong absorptions at 3360; 3280',2980; 2860; 1630; 1440; I350; 1290; l240; H90; 765 and 710cm.

The 2-ethylimino-3-(2-phenylacetylamino-2- phenylethyl)thiazolidine usedas starting material was obtained as follows:

N-( 2-Phenylacetylamino-2-phenylethyl )ethanolamine-O-sulphate (18.9g.)was dissolved in 2N-sodium hydroxide (25ml.) and water (25ml.). Ethanol(25ml.) and ethyl isothiocyanate (4.35g.) were added. The pH of thesolution was then maintained at 9 :t 0.5 by the addition of 2N-sodiumhydroxide until a total of 25ml. had been added. Water (25ml.) was thenadded, and the mixture was filtered. The solid residue was washedsuccessively with water (50ml.) and petroleum ether (b.p.6080C., 50ml),and dried at 50C. to give 2- ethylimino-3-(2-phenylacetylamino-2-phenylethyl thiazolidine. A sample crystallisedfrom petroleum 9 ether (b.p.ll20C.) had m.p.l42l44C.

EXAMPLE l62-lsoamylimino-3-(Z-phenylacetylamino-2-phenylethyl)thiazolidine (2.2g.)was dissolved in N-hydro- 5 chloric acid (ml.) and the solution refluxedfor 10 from isopropanol (5ml.). The resulting tetramisole hy- 0drochloride was filtered 01 i; washed successively with isopropanol(2ml.) and ether (l0ml.), and dried at 50C., and it then hadm.p.250-258C.

EXAMPLE 12 3-( Z-Phenylacetylamino-2-phenylethyl)-2-isopropyliminothiazolidine (7.0g.) was dissolved in 5N-'hydrochloric acid (30ml.), and the solution was refluxed for 10 hours.The solution was evaporated to dryness at mm., and the residuecrystallised from ethanol (ml. washed with ethanol (5ml.), and dried at50C. to give 3-( 2-amino-2-phenylethyl)-2-isopropyliminothiazolidinedihydrochloride, m.p.2062 1 1C. (decomposition).

The thiazolidine derivative used as starting material was prepared usingisopropyl isothiocyanate by an analogous method to that described forthe ethyl homologue in Example 10. It had m.p.l12-l 14C. afterrecrystallisation from petroleum ether (b.p.l00-l20C.).

EXAMPLE 13 3-(2-Amino-2-phenylethyl)-2-isopropyliminothiazolidine(0.5g.) was placed in a small tube, and the tube was plunged into an oilbath at 245C. and held at that temperature for 5 minutes. The sample wasthen removed, cooled to room temperature, triturated with boilingisopropanol (3ml.) and allowed to cool. The mixture was filtered, andthe solid residue washed successively with isopropanol (1 ml.) andacetone 2m1.) to give tetramisole hydrochloride, m.p.255258C.

EXAMPLE 14 2-lsobutylimino-3-( 2-ph enylacetylamin o-2-phenylethyl)thiazolidine (7.6g.) was dissolved in SN-hydrochloric acid(30ml.) and the solution was refluxed for 9 hours. The solution was thencooled to 40C. and washed with chloroform (30ml. The aqueous solutionwas evaporated to dryness at 15mm. The residue was crystallised fromisopropanol l5ml.), and then washed with isopropanol (5ml.) and dried at50C. There was thus obtained2-isobutylimino-3-(2-amino-2-pheny1ethyl)thiazolidine dihydrochloride,m.p. l 88-190C.

The thiazolidine derivative used as starting material was prepared inanalogous fashion to the ethyl homologue (see Example 10). It hadm.p.153-154C. after crystallisation from petroleum ether(b.p.l00-120C.).

EXAMPLE 15 2-lsobutylimino-3-( Z-amino-Z-phenylethyl)thiazolidinedihydrochloride (0.5g.) was dissolved in dimethylforrnamide (2ml.) andthe solution was heated at 120C. for 40 hours. The reaction mixture wasthen allowed to cool, the resulting mixture wsa filtered and thecrystalline solid residue was successively washed with isopropanol(2ml.) and ether (5ml.) and dried at 50C., to give tetramisolehydrochloride, m.p.257-259C.

hours. The solution was evaporated to dryness at l5mm., the residuecrystallised from isopropanol (10ml.), washed with isopropanol (2ml.),and dried at 50C. There was thus obtained 2-isoamylimino-3-(2-amino-Z-phenylethyl)thiazolidine dihydrochloride, m.p. 192-l98C.(decomposition).

The thiazolidine derivative used as starting material was prepared inanalogous fashion to the ethyl homologue (see Example 13). it had m.p.-137C. after crystallisation from petroleum ether (b.p. l00-l20C.).

EXAMPLE l7 2-ls0amylimino- 3-( 2-amino-2-phenylethyl )thiazol idinedihydrochloride (0.20g.) was dissolved in water (5ml.) and the solutionrefluxed for 24 hours. After evaporation to dryness at l5mm., theresidue was crystallised from isopropanol (2ml.), the product washedsuccessively with isopropanol (lml.) and ether (5ml.) and dried at 50C.,to give tetramisole hydrochloride, m.p.256259C.

EXAMPLE [8 2-( 3-Pentylimino)-3-( 2-phenylacety lamino-2-phenylethyl)thiazolidine hydrochloride (2.5g) was dissolved inSN-hydrochloric acid 10ml.) and the solution refluxed for 10 hours andthen evaporated to dryness at 15mm. The residue was crystallised fromisopropanol (10ml.), washed successively with isopropanol (2ml.) andether (5ml.), and dried at 50C. There was thus obtained2-(3-'pentylimino)-3-(2-amino-2- phenylethyhthiazolidinedihydrochloride, m.p. l97-20lC. (decomposition).

This hydrochloriide (0.5g.) was dissolved in water (5ml. and aqueousammonia solution (specific gravity 0.880) was added to pH 9. Theprecipitated oil was extracted with methylene chloride (20ml.), and theextract dried (MgSO and evaporated to dryness at 15mm. to give2-(3-pentylimino)-3-(2-amino-2- phenylethyl)thiazolidine as a colourlessoil. The infrared spectrum of the oil showed strong absorption at 3390;3000; 2960; 2900; l640', 1458; 1295; 1245 and 710cm.

The 2-( 3-pentylimino)-3-( 2-phenylacetylamino-2-phenylethyl)thiazolidine hydrochloride used as starting material wasprepared as follows:

N-( 2-Phenylacetylamino-2-phenylethyl )ethanolamine-O-sulphate (6.43g.)was dissolved in N-sodium hydroxide (l7ml.), and a solution of 3-pentylisothiocyanate (2.2g.) in ethanol (15ml.) was added. Further N- sodiumhydroxide (l7ml.) was then added, and the solution was stirred for 18hours at 25C. and then refluxed for 2 hours. After cooling to roomtemperature, the reaction mixture was extracted with methylene chloride(50ml.) and the organic extract was evaporated to dryness at 15mm. Theresidue was dissolved in acetonitrile (15ml. and hydrogen chloride gaswas passed through the solution until the pH fell to 2 to 3. The productwas then precipitated from the solution by addition of ether (15ml.) andwas filtered off, washed with ether (20ml.) and dried at 50C. A samplecrystallised from ethyl acetate had m.p. l45-148C.

EXAMPLE l9 2-( 3-Pentylimino)-3 2-amino-2-phenylethyl thiazolidine(0.4g.) was dissolved in water (5ml.) by adding 70% w/w perchloric acidto pH 4. The solution was then refluxed for l hours, cooled to roomtemperature, basified to pH 12 with l8N-sodium hydroxide, extracted withmethylene chloride (20ml. and the extract evaporated to dryness at 15mm.The residue was dissolved in isopropanol (ml.) and the solutionacidified to pH 2 with hydrogen chloride gas. The mixture was filtered,and the solid residue washed successively with isopropanol (2ml.) andether (5ml.), and dried at 50C. to give tetramisole hydrochloride,m.p.2S7-259C.

EXAMPLE 20 2-Allylimino-3-(2-phenylacetylarnino-2-phenylethyll-thiazolidine (g) was dissolved inSN-hydrochloric acid (40ml.), and the solution was refluxed for 9 hours.The solution was cooled to 40C. and washed with chloroform (50ml. Theaqueous phase was evaporated to dryness at lSmm. to give2-allylimino-3-(2- amino-2-phenylethyl)thiazolidine dihydrochloride. Asample crystallised from a H v/v mixture of isopropanol andtetrahydrofuran had m.p. l68l75C. (decomposition).

The thiazolidine derivative used as starting material was prepared inanalogous manner to the ethyl analogue (see Example 10). A samplecrystallised from a lzl v/v mixture of toluene and petroleum ether(b.p.100-l20C.) had m.p. l38-l40C.

EXAMPLE 2l 2-Allylimino-3-(2-amino-2-phenylethyl)thiazolidinedihydrochloride (0.5g.) was dissolved in water (5ml.), and the solutionwas refluxed for 30 hours. The solution was evaporated to dryness atl5mm., and the residue was crystallised from isopropanol (5ml.) andwashed successively with isopropanol (lml.) and ether (5ml.), to givetetramisole hydrochloride, m.p. 256-259C.

EXAMPLE 22 2-Ethylimino-3-( 2-amino-2-phenylethyl )thiazolidine (0.65g.)was dissolved in water lOml.) by the addition of p-toluenesulphonic acidmonohydrate to pH 4. The resulting solution was refluxed for 24 hoursand then evaporated to dryness at l5mm. The residue was crystallisedfrom isopropanol (5ml.), and the crystals washed successively withisopropanol (2ml.) and ether (5ml.) and dried at 50C. to givetetramisole p-toluenesulphonate, m.p. l59l60C.

EXAMPLE 23 Sulphuric acid (68ml) was added dropwise, with vigorousstirring and cooling, to acetonitrile (29ml), maintaining thetemperature below C. When all of the acid had been added,N-(2-hydroxy-2-phenylethyl- )ethanolamine (45.25g.) was added in smallportions to the mixture, maintaining the temperature below C. andstirring continuously. The reaction mixture was stirred at 20-25C. for 4hours, and then poured into a mixture of water (450ml) and toluene(50ml.). An azeotropic mixture of toluene, acetonitrile and water wasthen distilled from the solution until the vapour temperature reachedl00C. The distillation was stopped and the solution refluxed for 5hours. Nitrogen 12 was then passed over the solution which was cooled tobelow 60C. while lSN-sodium hydroxide was added to pH 12. Thetemperature was then adjusted to 35C. and methylene chloride lSOml.)added. The organic phase was separated and the aqueous solutionextracted with three further 50ml. portions of methylene chloride. whilemaintaining the temperature of the solution at 35C. in a nitrogenatmosphere. The combined methylene chloride extracts were thenazeotroped until dry and a total of l50ml. of methylene chloride wasdistilled off. The solution of N-( 2-amino-2-phenylethyl)ethanolamine soobtained was then half neutralised with hydrogen chloride gas, and addedover 30 minutes to a stirred mixture of thionyl chloride (20ml.) andmethylene chloride (50ml.) at 25-30C. The reaction mixture was stirredat 2025C. for 16 hours and then comprised N-( 2-amino- 2-phenylethyl)-2-chloroethylamine. A solution of thiourea (15.2g.) in water (300ml)was added. The methylene chloride was separated and discarded, and thesolution was refluxed under nitrogen for 17 hours. In order to completethe cyclisation of the intermediate 2-imino-3-( 2-amino-2-phenylethylthiazolidine to tetramisole, the pH of the solution was then adjusted to3.5 to 4.0 by the addition of ISN- sodium hydroxide, and the solutionwas refluxed for a further 5 hours under nitrogen. The pH of thesolution was then adjusted to l l to 12 by addition of ISN- sodiumhydroxide, and the solution was extracted with toluene (l00ml., followedby 50ml.). The combined extracts were dried (Na SO activated carbon (2.5g.) was added, the mixture was filtered, and the solid resi due waswashed with toluene (25ml. To the combined filtrate and washing wasadded isopropanol (35ml), and hydrogen chloride was passed through thesolution to pH 2 to 3. The mixture was allowed to cool to roomtemperature, and the resulting mixture filtered. The solid residue waswashed with isopropanol (25ml.) and dried at 50C. to give tetramisolehydrochloride. A sample crystallised from ethanol had m.p.258-260C.

EXAMPLE 24 N-( 2-Amino-2-phenylethyl )-2-chloroethylaminedihydrochloride (2.715g.) was dissolved in water (l5ml.), and potassiumthiocyanate (0.97g.) was added. The solution was then heated at 80C. for16 hours, and then cooled to room temperature, made basic to pH 11 withl8N-sodium hydroxide, and extracted with methylene chloride (2 X 20ml.).The combined extracts were dried (M1 80 filtered, and a 3N solution ofhydrogen chloride in isopropanol added O the filtrate to pH 2. Thesolution was set aside crystallisation was complete. The crystals wetfiltered off, washed successively with isopropanol (f -l and acetone10ml.). and dried at 50C jog-" Crude ramisole hydrochloride. A samplpcrystallised from ethanol had m.p.258-260C, a

The amino derivative used as starting material was prepared as follows:I

Crude N-( 2-amino-2-phenylethyl lethanolamme, (prepared by the methoddescr b d n x mple 23 and isolated by evaporation of the methylenechloride extract to dryness at 15mm, and containing 887g of thecompound) was dissolved in ethylene dichloride (450ml). The solution wassaturated with hydrogen chloride gas with vigorous stirring, and thionylchloride (58.6ml.) was added dropwise at 50C. over half an hour. Thetemperature was then raised to C. for 2 hours, and isopropanol (60ml)was then added dropwise. The reaction mixture was allowed to cool to25C., and the resulting mixture was filtered. The crystalline residuewas washed successively with ethylene dichloride (50ml.) and acetone(50ml.), and dried at 70C. to giveN-(2-amino-2-phenylethyl)-2-chloroethylamine dihydrochloride. A samplecrystallised from lzl v/v methanol-ethanol had m.p.l94l96C. (sealedtube).

EXAMPLE 25 N-( 2-amino-2-phenylethyl )-2-chloroethylaminedihydrochloride (5.43g.) was dissolved in water (lOml.) and ethanol(20ml.), and a solution of phenyl isothiocyanate (2.7g.) in ethanol(lml.) was added. The pH of the solution was adjusted to 5.5 by additionof 2N sodium hydroxide, and maintained at that value for 4 hours. Thesolution was acidified to pH 1 with concentrated hydrochloric acid, andevaporated to dryness at 15mm. The residue was extracted with ethanol(lOOmL) under reflux, and the mixture obtained was filtered and thefiltrate evaporated to dryness at lmrn. The residue was dissolved inisopropanol (5ml.), and the solution was diluted with tetrahydrofuran(500ml.) and allowed to stand for 5 days. The crystals which separatedwere filtered off, washed with ether lOml.), and dried at roomtemperature, to give 2-phenylimino-3-(2-amino-2-phenylethyl)thiazolidine dihydrochloride, m.p.l83-l86C.

EXAMPLE 26 was filtered off, washed with acetone (5ml.), and dried at50C., to give tetramisole hydrochloride, m.p.257-259C.

EXAMPLE 27 N-(2-Amino-2-phenylethyl)-2-bromoethylaminedip-toluenesulphonate (587g), thiourea l. l4g.), p-toluenesulphonic acid(0.57g.) and water (l5ml.) were refluxed together for 18 hours.2N-Sodium hydroxide (1.85ml.) was then added and the solution refluxedfor a further 6 hours. 2N-Sodium hydroxide was then added to pH l2, andthe mixture set aside until crystallisation was complete. The crystalswere filtered off, washed with water (20ml), and dried at roomtemperature to give tetramisole. A sample crystallised from cyclohexanehad m.p.92-93C.

The starting material was prepared as follows:

Crude N-( 2-amino-2-phenylethyl )ethanolamine (prepared by the proceduredescribed in Example 23 and isolated by evaporation of the driedmethylene chloride extracts to dryness at mm; and containing 370g. ofthe compound) was dissolved in ethylene dichloride (200ml.), and 48% w/waqueous hydrobromic acid (25.5ml.) was added. The solution wasazeotroped at 78C. until it was anhydrous, and the residue was addeddropwise over I hour to a mixture of ethylene dichloride (50ml.) andphosphorus tribromide (28.6ml.) at 40C. The reaction mixture was thenstirred for l6 hours at 25C lsopropanol (400ml) was added, and thesolution decanted from an insoluble gum. p-Toluenesulphonic acid(76.0g.) was then added to the solution, and, after stirring for 2hours, the product [N-(2-amino-2-phenylethyl)-2-bromoethylaminedi-p-toluenesulphonate] was filtered off, washed successively withisopropanol (50ml) and ether 100ml), and dried at room temperature, andthen had m.p.l90-l92C.

EXAMPLE 28 2-lmino-3-( 2-benzoylamino-2-phenylethyl)thiazolidinehydrochloride (l.0g.) was suspended in 2N-sulphuric acid (50ml.), andthe mixture was refluxed for six days. The mixture was then cooled toroom temper ature, basified to pH l2 with l8N-sodium hydroxide,extracted with toluene (25ml.), and to the toluene extract was added a3N-solution of hydrogen chloride in isopropanol to pH 2. Theprecipitated product was filtered off, washed with toluene lOml.), driedat C., dissolved in water (5ml.), and basified to pH 12 with lSN-sodiumhydroxide. The precipitated tetramisole was filtered off, washed withwater 10ml.) and dried at 40C., and then had m.p. 9293C.

The starting material was obtained as follows:

N-( 2-Benzoylamino-2 -phenylethyl ethanolamine-O- sulphate (35.0g.) wasadded to a mixture of a solution of sodium hydroxide (ll.2g.) in water(200ml.) and toluene (200ml.), and the mixture was stirred under refluxfor 2 hours. After cooling to room temperature, the mixture wasseparated, the aqueous phase extracted with toluene (200ml.), and thecombined organic phase and the organic extract dried (MgSO andevaporated to dryness at 15mm. There was thus obtained crudeN-(2-benzoylamino-2-phenylethyl)aziridine.

This aziridine derivative 1 1.4g.) was dissolved in toluene (200ml.),and a solution of potassium thiocyanate (4.75g.) and concentratedhydrochloric acid 15ml.) in water (lml.) was added. The mixture wasstirred and refluxed for 4 hours, and then cooled to room tempe rature.The mixture was filtered, and the solid residue washed successively withwater (l0ml.) and toluene (lOml.), and then dried at 60C. The solid wassuspended in a mixture of 2N-sodium hydroxide (l20ml.) and toluene (ml),and the resulting mixture stirred under reflux for 30 minutes, cooled toroom temperature, and separated. The aqueous phase was extracted withfurther toluene (l00ml.) and the combined organic phase and extract wasdried (MgSO and evaporated to dryness at 15mm. The residue was dissolvedin toluene (25ml) and to it was added a 3N solution of hydrogen chloridein isopropanol to pH 2. The precipitate was filtered off, washed withtoluene (2 X l5ml.), and dried at 70C., to give 2-imino -3-(2-benzoylamino-Z-phenylethyl)thiazolidine hydrochloride, m.p.257260C.

EXAMPLE 29 3-(2-Amino-2-phenylethyl)-2iminothiazolidine di hydrochloride(4g.) was dissolved in water (l0ml.) at 98C., and the pH was adjusted to7 with ION-sodium hydroxide. After 1 minute, the solution wasfreezedried to yield a white solid comprising 2-amino-3-(2-mercaptocthyl)-5-phenylimidazolc hydrochloride. The infra-red spectrumof this product in purified liquid paraffin (Nujol; the word Nujol is atrade mark) was as follows:

Position (cm. "J intensity Assignment 3330} medium strong NH stretch3260 3080 strong N-H stretch 2540 weak S-H stretch I675 strongC=Nstretch (disubstituted guanidinium*l) I608 medium strong NH in planebending I575 strong C=N stretch (disubstituted guanidinium*ll) 1498medium phenyl nucleus 770 medium monosubstituted phenyl 705 mediumstrong out of plane bending These three bands are coupled vibrationsinvolving C=N and C N vibrations.

EXAMPLE 30 N-(2-hydroxy-2-phenylethyl)-2-chloroethylamine hydrochloride(4.7g.) was added, with stirring at C., to a mixture of acetonitrile(5.0g) and 98% w/w sulphuric acid (l7.5g.), and stirring was continuedfor four hours. The reaction mixture was diluted with icecold water(50ml.) and basified to pH 9 with l8N- sodium hydroxide, keeping thetemperature below 20C. The solution was extracted with chloroform (50ml.and the extract was dried (MgSO and evaporated to dryness at 15mm. togive N-(2-acetylamino-2' phenylethyl)-2-chloroethylamine as a gum. Thenuclear magnetic resonance spectrum of the product indeuteriochloroform, using tetramethyl silane as internal standard,showed the following absorptions: 2.75 p.p.m. (singlet, protons); (4.95p.p.m. (multiplet, l proton); 5.6 p.p.m. (singlet, 2 protons); 6.5p.p.m. (triplet, 2 protons); 7.1 p.p.m. (multiplet, 4 protons); 8.05p.p.m. (singlet, 3 protons).

EXAMPLE 3 l 2Benzylimino-3-( 2-acetylamino-2-phenylethyl thiazolidine(5.7g) was dissolved in SN-hydrochloric acid (25ml), and the solutionwas refluxed for 16 hours. The solution was cooled to 20C., filtered toremove insoluble material and the filtrate evaporated to dryness at mm.The gum obtained was dissolved in isopropanol (30ml), toluene (ml.) wasadded, and the solution was evaporated at l5mm. The residue wasdissolved in refluxing isopropanol (l5ml.), and the solution allowed tocool. The resulting mixture was filtered, and the solid residue,2-benzylimino-3-( 2-amino- Z-phenylethyl )thiazolidine dihydrochloride,was washed successively with isopropanol (5ml.) and ether (10ml) anddried at room temperature, and then had m.p. l90-l 94C. (decomposition).

The thiazolidine derivative used as starting material was prepared usingbenzyl isothiocyanate by an analogous method to that described for themethyl compound in Example 5. The product was not crystalline and wasused without further purification.

EXAMPLE 32 2-Benzylimino 3-( 2-amino-2-phenylethyl )thiazolidinedihydrochloride (1.0g.) was dissolved in water (l0ml.), and the solutionwas refluxed for 24 hours. The solution was cooled to 5C., basified withl8N- sodium hydroxide to pH 12 and the precipitated tetramisole filteredoff, washed with water (20ml.) and dried at room temperature. Theproduct had mp. 9293C. after recrystallisation from cyclohexane.

EXAMPLE 33 2-lmino-3-[ 2-acetamido-2-( 3-acetamidophenyl)ethyl]-thiazolidine (prepared as described below) was dissolved inSN-hydrochloric acid (20 ml.), and the solution was refluxed for l0hours and then evaporated to dryness at 15mm. The residue was dissolvedin warm ethanol (l0ml.) and the solution allowed to cool to roomtemperature. The resulting mixture was filtered, and the crystallineresidue washed with ethanol (2ml.) and dried at room temperature, togive 2-imino-3-[2- amino-2-( 3-aminophenyl )ethyl ]thiazolidine trihydrochloride, mp. 21 l2l5C. (decomposition).

The acetamido derivative used as starting material was obtained asfollows:

2-lmino-3- 2-hydroxy-2-( 3-acetamidophenyl )ethy l thiazolidine (2.37g.)was dissolved in acetonitrile (2.8g), and 98% w/w sulphuric acid(10.2g.) was added dropwise with stirring while maintaining thetemperature below 20C. The resulting solution was stirred at roomtemperature for 4 hours, then poured onto ice and basified to pH 12 withlSN-sodium hydroxide, maintaining the temperature below 10C. by theaddition of ice. The solution was extracted with methylene dichloride (2X 25ml.) and the combined extracts dried (MgSO and evaporated to drynessat 15mm. to give crude 2-imino-3-[2-acetamido-2-(3- acetamidophenyl)ethyl lthiazolidine.

EXAMPLE 34 2-lmino-3- 2-amino-2-( 3-aminophenyl )ethyl thiazolidinetrihydrochloride (0.13g.) was dissolved in water (5ml.), and thesolution refluxed for l7 hours. The solution was cooled to roomtemperature, basified with l8N-sodium hydroxide to pH l2, and extractedwith methylene dichloride (2 X 10ml. The combined extracts were dried(MgSO and evaporated to dryness at 15mm. The residue was dissolved inmethanol (2ml.) and the solution acidified to pH 1 with a 3N- solutionof hydrogen chloride in isopropanol. The resulting mixture wasevaporated to dryness at 15mm, the residue rendered solid by triturationwith acetonitrile (3ml.), and the product filtered off. washed withacetonitrile lml.) and dried at room temperature. The product, 6-(3-aminophenyl )-2,3,5,6-tetrahydroimidazo[2,l-b]-thiazoledihydrochloride, was cha racterised by its mass spectrum which showed amolecular ion of mass 219.0833 (corresponding to a molecular formula ofC,,H, N S) and fragment ions of approximate masses 218 (corresponding toC, H, N S), 191 (C H N S or C H N S), 163 (C H N- S), 127 (C H N S), 102(C H N- s) and 45 (CHS).

What we claim is:

l. A compound which is a member selected from the group consisting ofdiethylamine derivatives of the formula:

NHCOR wherein R is a member selected from the group consisting ofphenyl, nitrophenyl, aminophenyl and tolyl, and R is a member selectedfrom the group consisting of hydrogen, alkyl of not more than fivecarbon atoms, phenyl and benzyl and Y is a member selected from thegroup consisting of chlorine, bromine and hydrogensulphate.-

4. A compound as claimed in claim 1 which is N-(2-acetylamino-Zphenylethyl )ethanolamine-O-sulphate.

5. A compound as claimed in claim 1 which IS N-(2-phenylacetylamino-2-phenylethyl )ethanolamine-O-sulphate.

6. A compound as claimed in claim 1 which 18 N-(2-benzoylamino-Z-phenylethyl)ethanolamine-O-sulphate.

7. A compound as claimed in claim 1 which is N-(2-acetylamino-2-phenylethyl )-2-chloroethyl amine

1. A COMPOUND WHICH IS A MEMBER SELECTED FROM THE GROUP CONSISTING OFDIETHYLAMINE DERIVATIVES OF THE FORMULA:
 2. A compound as claimed inclaim 1 wherein R1 is a member selected from the group consisting ofphenyl, m-nitrophenyl, m-aminophenyl and m-tolyl, and R3 is a memberselected from the group consisting of hydrogen, alkyl of not more thanfive carbon atoms, phenyl and benzyl, and Y is a member selected fromthe group consisting of chlorine, bromine and hydrogen-sulphato.
 3. Acompound as claimed in claim 2 wherein R1 stands for phenyl.
 4. Acompound as claimed in claim 1 which isN-(2-acetylamino-2-phenylethyl)ethanolamine-O-sulphate.
 5. A compound asclaimed in claim 1 which isN-(2-phenylacetylamino-2-phenylethyl)ethanolamine-O-sulphate.
 6. Acompound as claimed in claim 1 which isN-(2-benzoylamino-2-phenylethyl)ethanolamine-O-sulphate.
 7. A compoundas claimed in claim 1 which isN-(2-acetylamino-2-phenylethyl)-2-chloro-ethylamine.